Q J Med 2000; 93: 45-53
© 2000 Association of Physicians
Klebsiella pneumoniae meningitis: timing of antimicrobial therapy and prognosis
1 From the Departments of Internal Medicine and 2 Laboratory Medicine, National Taiwan University Hospital, and 3 Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
Received 4 August 1999
Dr S.-C. Chang, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan. e-mail: sc4030{at}ha.mc.ntu.edu.tw
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Summary |
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We analysed the clinical course of 30 adult patients with Klebsiella pneumoniae meningitis, 18 community-acquired and 12 hospital-acquired, to assess whether the timing of appropriate antimicrobial therapy had a major effect on prognosis. Of the 30 patients, 29 received appropriate antibiotics. The time from initial symptoms to the start of appropriate therapy, antibiotic resistance of K. pneumoniae isolates, underlying disease severity, diabetes mellitus, age, gender, and acquisition settings were all not significantly correlated with outcome. However, a Glasgow coma scale (GCS) score of 7 points or less at the start of appropriate antimicrobial therapy was a valid predictor of death or a permanent vegetative state (sensitivity 82%, specificity 93%, p=0.005), even after adjusting for the effect of confounding variables by logistic regression. Timing of appropriate antimicrobial therapy, as defined by consciousness level but not by symptom duration, is a major determinant of survival and neurological outcome for patients with K. pneumoniae meningitis, and the first dose of an appropriate antibiotic should be administrated before their consciousness deteriorates to a GCS score of 7 points or less.
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Introduction |
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Klebsiella pneumoniae, a pathogenic encapsulated Gram-negative bacillus, has gained an increasingly important role in adult meningitis both in community-acquired and hospital-acquired settings over the past 30 years.1–3 Many patients are susceptible to K. pneumoniae meningitis, including patients with diabetes mellitus, debilitating diseases, extrameningeal K. pneumoniae infections, K. pneumoniae bacteraemia, and patients with head injury or who have undergone neurosurgical procedures, with or without cerebrospinal fluid (CSF) leakage.4–7 In Taiwan, K. pneumoniae is one of the most common causative pathogens of community-acquired bacterial meningitis.8 Despite the use of potent antibiotics with excellent in vitro activity such as third-generation cephalosporins, the case fatality rate of K. pneumoniae meningitis remains high at 30–40%.9,10 Survivors may suffer from long-term severe neurological sequelae.9,10
The timing of appropriate antimicrobial therapy may be an important factor related to survival and neurological outcome. However, there is a lack of data from previous studies on this issue.2–5,9,12 Timing of therapy can be defined as the time from the initial symptoms to the start of therapy. Although intuitive, this definition has some drawbacks, since the occurrence of the initial symptoms does not necessarily equate to the onset of meningitis. For community-acquired K. pneumoniae meningitis, determination of onset of meningitis by initial symptoms is especially problematic, since extra-meningeal K. pneumoniae infections often precede the development of metastatic meningitis.4–6 Furthermore, symptom appearance reported by patients or family may not be accurate. An alternative way to define the timing of therapy is based on the severity of meningitis at the start of therapy. Since untreated K. pneumoniae meningitis will run a progressive deteriorating course and is almost universally fatal,13,14 the severity of physiological derangement can serve as an objective indicator of the stage of disease.
To explore whether the timing of appropriate antimicrobial therapy had a major impact on the prognosis of K. pneumoniae meningitis, we studied the outcome and prognostic factors of all adult patients with a diagnosis of K. pneumoniae meningitis who were treated at our hospital over the past 13 years. Both symptom duration and severity of meningitis at the start of appropriate antimicrobial therapy were analysed. The effect of other factors which may influence the outcome, such as production of extended-spectrum beta-lactamase (ESBL) by K. pneumoniae,15 severity of underlying diseases, age, acquisition settings, and various demographic and clinical factors, were also studied.
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Methods |
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We analysed the medical records of all adult (age
16 years) patients with K. pneumoniae meningitis diagnosed and treated at the National Taiwan University Hospital (NTUH) from January 1986 to April 1999. The NTUH is a university-affiliated general hospital with a 1800-bed capacity, providing both primary and tertiary referral care of patients.
Identification of K. pneumoniae meningitis cases
The cases of K. pneumoniae meningitis were retrospectively identified through two methods. First, the list of all adult patients with a discharge diagnosis of bacterial meningitis (ICD-9 code 320) was obtained using the computer database of discharge diagnoses. Second, the list of all patients with K. pneumoniae isolated from CSF culture was obtained using the computer database of clinical bacterial isolates. The medical records of these patients were then reviewed and the cases that met the inclusion criteria were included in this study.
Inclusion criteria
To be included as a case of K. pneumoniae meningitis, K. pneumoniae must have been isolated either from CSF culture or from blood cultures taken during the initial diagnostic work-up for meningitis; and there should have been no other pathogen in the CSF and blood. In addition, the following two clinical criteria had to be met: (i) clinical presentation with acute onset of fever, plus neck stiffness, positive Kernig's sign, and/or consciousness disturbance; and (ii) pleocytosis with neutrophil predominance, hypoglycorrhachia, and/or increased protein level in CSF.
Data
The following data were obtained from the medical records of each of the included cases of K. pneumoniae meningitis: demographic and clinical information, laboratory results, candidate prognostic factors, timing and choice of antimicrobial therapy, antimicrobial susceptibility of the K. pneumoniae isolates, and outcome.
Classification of acquisition settings and underlying diseases
Hospital-acquired vs. community-acquired meningitis was classified according to the Centers for Disease Control definitions for nosocomial infections.16 Spontaneous meningitis denoted meningitis not related to head injury or neurosurgery. The severity of underlying diseases was classified as non-fatal, ultimately fatal, or rapidly fatal, according to the McCabe-Jackson criteria.17
Definition of appropriate antimicrobial therapy
Antimicrobial susceptibility testing of the K. pneumoniae isolates was performed by the disk diffusion method according to the National Committee of Clinical Laboratory Standards.18 The E test ESBL screen was used to enhance the detection of ESBL-producing isolates if the isolate was resistant to cefazolin but had borderline susceptibility to cefotaxime.19,20 The isolates were classified as resistant to third-generation cephalosporins if ESBL-related resistance phenotype was confirmed by E test ESBL screen. Appropriate antimicrobial therapy was defined as the use of bactericidal agents which can reach therapeutic concentrations in the central nervous system and to which the isolated pathogens were susceptible in vitro, in a dosage adequate to treat meningitis.
Definition of symptom duration and severity of meningitis
Symptom duration before treatment was defined as the duration from the first occurrence of fever, headache, or consciousness disturbance, to the first dose of appropriate antimicrobial therapy. The severity of meningitis at the start of appropriate antimicrobial therapy was assessed by three different sets of physiological parameters: (i) the Glasgow coma scale (GCS) for consciousness,21 (ii) sepsis and septic shock for systemic inflammatory responses,22 and (iii) Acute Physiology and Chronic Health Evaluation (APACHE) II score for overall physiological derangement.23 The terms sepsis, severe sepsis, and septic shock were defined according to the 1992 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee definition of sepsis and septic shock.22 APACHE II scores were calculated by the original scoring system,23 but to enhance the applicability of this scoring system to the present patient group, modification was allowed to assign zero points to the items `PaO2' and `pH' if the attending physicians did not perform arterial blood gas analysis due to the absence of cyanosis or respiratory distress. For comparison, consciousness and systemic inflammatory responses recorded at the initial medical evaluation were also obtained.
Definition of outcome
Outcome was classified into two categories: good (survival with no or minor neurological deficit) and poor (death or a permanent vegetative state). For patients who survived but had neurological sequelae, the neurological outcome was classified according to the status at discharge from hospital. Neurological deficits that did not interfere with the independence of daily living and self-care were classified as minor. A vegetative state was defined as persistent coma with a total dependence on other persons.
Statistical methods
Fisher's exact test was used to examine the statistical significance of binary variables, including predisposing conditions and candidate prognostic factors. Both Student's t test (parametric) and the Mann-Whitney test (non-parametric) were used to compare difference in symptom duration between two groups. Both Pearson's r (parametric) and Spearman's r (non-parametric) tests were used to examine the correlation between symptom duration and severity of meningitis. The logistic regression model (SPSS for Windows, Release 8.0) was used to adjust for the effects of other variables on the main parameters of interest.
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Results |
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Demographic features and predisposing conditions
A total of 30 adult patients with K. pneumoniae meningitis were identified during the period January 1986 to April 1999, including 18 community-acquired cases and 12 hospital-acquired cases. Seventeen of these 30 cases were spontaneous and 13 cases were head-injury- or neurosurgery-related. The demographic characteristics and predisposing conditions of these cases are summarized in Table 1
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All patients led an active daily life prior to hospitalization. Patients with community-acquired K. pneumoniae meningitis were more likely to have preceding extrameningeal K. pneumoniae infections (p=0.01). The sites of preceding extrameningeal K. pneumoniae infections included pyogenic liver abscess, septic endophthalmitis, pneumonia, otitis media, urinary tract infection, lumbar discitis, and perianal abscess. Patients with hospital-acquired K. pneumoniae meningitis were more likely to have undergone a neurosurgical procedure or to have CSF rhinorrhea (p=0.004). The reasons for neurosurgical procedure included pituitary adenoma, other intracranial tumors, vascular malformation, and head injury. The causes of CSF rhinorrhea included neurosurgical procedure, head injury, and nasopharyngeal carcinoma.
According to the McCabe-Jackson criteria, the underlying diseases were classified as non-fatal in 26 patients. Four patients had an ultimately fatal disease (nasopharyngeal carcinoma, orbital adenocarcinoma, non-Hodgkin's lymphoma, and pontine astrocytoma, respectively). None of the patients had a rapidly fatal underlying disease.
Clinical features and CSF findings
The initial clinical manifestations are summarized in Table 2. Patients with hospital-acquired K. pneumoniae meningitis were less likely to have neck stiffness (p=0.009). Otherwise, the clinical features were not significantly different between the two groups. Fever and headache were the most common presenting symptoms. The median duration from initial symptoms to the diagnosis of meningitis was longer in community-acquired cases (5 days, range 0–27 days) than in hospital-acquired cases (2 days, range 0–17 days), but this difference was not statistically significant. Among the 30 patients, 21 had disturbed consciousness at presentation, including six patients with a GCS score 
7 points at initial evaluation. Two patients had severe sepsis at initial evaluation.
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All 30 patients underwent lumbar puncture for CSF study. The CSF findings are summarized in Table 2
. There was no significant difference in CSF findings between the two groups. K. pneumoniae was isolated from CSF in 25/30 patients. In the remaining five patients, the diagnosis of K. pneumoniae meningitis was confirmed by isolation of K. pneumoniae from blood during initial diagnostic work-up for acute community-acquired meningitis with fever, neck stiffness, pleocytosis and elevated protein in CSF, and without other pathogen isolated.
Antimicrobial susceptibility of K. pneumoniae isolates
In 28 of the 30 patients, the K. pneumoniae isolates were susceptible to all cephalosporins and aminoglycosides. Only two patients, both with hospital-acquired meningitis, were infected by K. pneumoniae isolates with an ESBL-related resistance phenotype (resistant to cefotaxime but susceptible to cephamycins). Both of the K. pneumoniae isolates with an ESBL-related resistance phenotype were susceptible to imipenem and ciprofloxacin.
Antimicrobial therapy
Antimicrobial therapy was prescribed immediately after the diagnosis of meningitis in all patients. Initial antibiotic therapy for meningitis was appropriate in 27 patients. In another two patients, therapy was switched to an appropriate agent after culture results were reported. A total of 29 patients received appropriate antibiotics during the course of treatment. The remaining patient, who received penicillin G and chloramphenicol, died before culture results became available.
Third-generation cephalosporins (cefotaxime, ceftriaxone, or moxalactam) were used to treat meningitis in 28 patients infected by susceptible K. pneumoniae isolates. Two patients infected by K. pneumoniae with ESBL-related resistance phenotype were initially treated with ceftazidime and meropenem, respectively. After culture results became available, ceftazidime was changed to ciprofloxacin in one of these patients, while the other received meropenem throughout the course.
The duration of antibiotic therapy was at least 3 weeks in 23 patients, including two patients who received 6 weeks of therapy because brain abscess complicated the disease course. Seven patients died before the 3 weeks had passed. Two patients with brain abscess underwent surgical drainage in addition to antibiotic therapy.
Timing of appropriate antimicrobial therapy
The duration from the initial symptoms to the first dose of appropriate antibiotic therapy ranged from 0 to 27 days. The median duration was longer in the community-acquired group (5 days, range 1–27 days) than in the hospital-acquired group (3 days, range 0–17 days), but the difference was not statistically significant.
The GCS scores at the start of appropriate antibiotic therapy ranged from full (15 points) to three points. Ten patients had a GCS score of 7 points when the first dose of appropriate antibiotic was given. The GCS scores were not available in three patients, two of whom were recorded as lethargic and one of whom had missing data. All three of these patients survived without sequelae.
The status of systemic inflammatory responses at the start of appropriate antibiotic therapy ranged from sepsis to septic shock. Four patients had severe sepsis and two patients had septic shock when the first dose of appropriate antibiotic was administrated.
The APACHE II scores at the start of appropriate antibiotic therapy ranged from 0 to 32 points. Six patients had an APACHE II score of 20 points or higher when the first dose of appropriate antibiotics given. APACHE II score data were missing in nine patients, because APACHE II scoring was not part of diagnostic routine for patients not admitted to intensive care units. Eight of these nine patients without APACHE II score data survived without neurological sequelae.
Outcome and prognostic factors
Among 30 patients, ten patients died, two remained in a vegetative state, one survived with a minor neurological deficit, and 17 survived without obvious neurological sequelae. The case fatality rate was 33%. Of the ten fatal cases, seven died within one week after the development of initial symptoms.
The prognostic factors of the 30 patients with K. pneumoniae meningitis are listed in Table 3. Duration of symptoms >3 days before the start of appropriate therapy was not significantly associated with a worse outcome. The median duration of symptoms before appropriate therapy was not significantly different in patients with good outcome (3 days, range 0–27 days) and those with poor outcome (5 days, range 1–17 days) (p=0.41, Mann-Whitney test; p=0.97, Student's t test). However, all three physiological parameters at the start of appropriate therapy predicted the outcome with statistical significance as follows: GCS (p=0.0002), severe sepsis or septic shock (p=0.04), and APACHE II score (p=0.011). For a poor outcome, a GCS score of seven points or less at the start of appropriate therapy had a predictive power of 82% sensitivity and 93% specificity; severe sepsis or septic shock at the start of appropriate therapy had a predictive power of 45% sensitivity and 94% specificity; and an APACHE II score of 20 or higher at the start of appropriate therapy had a predictive power of 60% sensitivity and 100% specificity.
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Unlike severity of meningitis at the start of therapy, severity of meningitis at initial evaluation was not significantly correlated with outcome. Both a GCS score of 7 points or less (odds ratio 8.0, 95%CI 0.7–85.8, p=0.12) and severe sepsis/septic shock (odds ratio 3.8, 95%CI 0.3–47.6, p=0.54) at initial evaluation were not valid outcome predictors.
Patients with longer duration of symptoms prior to treatment did not necessarily have more severe meningitis at the start of treatment. The correlation between symptom duration and GCS scores at the start of appropriate therapy was not significant (Pearson's r=0.05, p=0.81; Spearman's r=–0.10, p=0.62). APACHE II score (Pearson's r=0.19, p=0.42; Spearman's r=0.20, p=0.41) and severe sepsis/septic shock (Pearson's r=0.12, p=0.54; Spearman's r=0.06, p=0.78) at the start of therapy were also not correlated with symptom duration prior to therapy.
All other factors measured were not significantly correlated with outcome. These included antibiotic resistance of K. pneumoniae isolates, severity of underlying disease, the presence of seizures, diabetes mellitus, extrameningeal infection foci, bacteraemia, age, gender, spontaneous vs. post-traumatic or post-operative meningitis, and community-acquired vs. hospital-acquired meningitis.
Logistic regression analysis
After adjusting for the effects of confounding variables, including underlying disease severity, ESBL resistance phenotype of K. pneumoniae isolates, diabetes mellitus, age, and acquisition settings, only GCS at the start of appropriate therapy continued to be a statistically significant outcome predictors (p=0.005). Severe sepsis/septic shock at the start of therapy (p=0.089) and APACHE II score at the start of therapy (p=0.9) became statistically non-significant after adjusting for the effects of confounding variables.
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Discussion |
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The most important finding of this study is that the timing of appropriate antibiotic therapy, as defined by consciousness level measured by GCS, is a major determinant of survival and neurological outcome of patients with K. pneumoniae meningitis. A GCS score of 7 points or less at the start of appropriate therapy predicts a poor outcome with 82% sensitivity and 93% specificity. In contrast, symptom duration prior to appropriate therapy was not significantly correlated with the outcome of K. pneumoniae meningitis.
Some of the variables not shown to be statistically significant outcome predictors in this study might actually be important. Lu reported that inappropriate antibiotic therapy is associated with mortality.9 But because almost all of the patients in this study received appropriate antibiotics, the appropriateness of antibiotics cannot be demonstrated to be statistically significant. Similarly, since only two patients had septic shock at the start of therapy and none had a rapidly fatal underlying disease in this study, the effects of these two important factors cannot be statistically judged. The species of the pathogen causing meningitis, K. pneumoniae in this study, is itself a factor related to outcome.24 Patients with Haemophilus influenzae meningitis often have a better outcome than those with Streptococcus pneumoniae or Gram-negative bacillary meningitis.24
Previous studies on the prognostic factors of K. pneumoniae meningitis have generated conflicting and confusing results. While Cherubin reported remarkable success with third-generation cephalosporin therapy,11 others reported that third-generation cephalosporins did not reduce mortality.10,12 Tang reported that spontaneous meningitis, age >60 years, diabetes mellitus, and severe neurological deficit at admission adversely affected mortality,10 but Lu concluded that only septic shock and inappropriate antibiotics were associated with mortality.9 Previous investigators also neglected the devastating consequences of a permanent vegetative state and classified this condition as survival, for which treatment was considered successful.11,12 The result of the present study showed that the timing of appropriate antibiotic therapy, as defined by consciousness level measured by GCS, was the major determinant of survival and neurological outcome in patients who received appropriate antibiotic therapy. This conclusion is biologically plausible, since deteriorated consciousness in meningitis is a marker of severe brain oedema and increased intracranial pressure, which is the major pathophysiological mechanism responsible for morbidity and mortality in bacterial meningitis.25,26 Our findings imply that the prognosis of patients with K. pneumoniae meningitis is improved if the first dose of appropriate antibiotic therapy is administrated before the consciousness of patients deteriorated to a GCS score of 7 points or less.
In this study, the poor correlation between symptom duration before therapy and outcome may be partially explained by the presence of preceding extrameningeal K. pneumoniae infections in eight patients. In these patients, it was difficult to determine the exact time when K. pneumoniae invaded the central nervous system. It is also possible that some patients had a more fulminant course and deteriorated more quickly than others. However, we also found that outcome was not determined by the severity of meningitis at initial evaluation. Prompt appropriate antimicrobial therapy as soon as possible is still strongly recommended.
Bacterial meningitis is a life-threatening disease even in the antibiotic era.24 A valid outcome-predicting method not only assists the design of clinical trials of new therapeutic strategies, but also facilitates patient management by identifying those in need of intensive treatments.27 Depressed consciousness level at admission has been found to be one of the most important prognostic factors in most previous studies.11,12,28–31,33,34 However, among these studies, the methods used to define consciousness level were often inaccurate and varied considerably.11,12,28,32 GCS is an accurate, well-validated neurological assessment.21 Initially developed for patients with head injury, GCS at admission has been recently shown to be a good prognostic indicator for adult patients with bacterial meningitis, according to the studies of Schutte and Garlicki.33,34 However, most patients enrolled in their studies had meningitis due to S. pneumoniae.33,34 Our results indicate that GCS can also be applied to predict the outcome of Gram-negative bacillary meningitis.
Consciousness level at admission may not be accurate enough for outcome predicting. The consciousness of patients may deteriorate rapidly over a period of several hours, and appropriate antimicrobial therapy may not be started immediately at admission in every patient.35 Since appropriate antibiotic therapy is the key to survival for patients with bacterial meningitis, consciousness level at the start of appropriate antibiotic therapy may be a more appropriate prognostic indicator than consciousness level at admission. This has been validated in the present study of patients with K. pneumoniae meningitis. For patients with bacterial meningitis due to other pathogens, the GCS scores at the start of appropriate therapy may similarly provide a more accurate prediction of outcome than the GCS scores at admission.
Patients with bacterial meningitis may deteriorate quickly. Clinical wisdom emphasizes the importance of prompt antimicrobial therapy,29 and some medical-legal cases have involved the possible failure to initiate treatment at an earlier stage of disease.36 However, no previous study has ever confirmed a clinically valid relation between timing of antimicrobial therapy and outcome. Aronin et al. recently explored this issue but found that delay in initiation of antibiotics did not significantly differ between those with or without adverse outcomes.32 This puzzling result can be plausibly interpreted in the context of our findings: what is important is not the time from the initial symptom to therapy, but the consciousness level at the start of effective antibiotic treatment.
We conclude that timing of appropriate antimicrobial therapy, as defined by consciousness level but not by symptom duration, is a major determinant of survival and neurological outcome for patients with K. pneumoniae meningitis. In patients with K. pneumoniae meningitis, the first dose of appropriate antibiotic should be given before the consciousness of the patient deteriorates to a GCS score of 7 points or less.
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